Underappreciated and complex role of nitrous acid in aromatic

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Environmental Processes

Underappreciated and complex role of nitrous acid in aromatic nitration under mild environmental conditions: the case of activated methoxyphenols Ana Krofli#, Matej Huš, Miha Grilc, and Irena Grgi# Environ. Sci. Technol., Just Accepted Manuscript • DOI: 10.1021/acs.est.8b01903 • Publication Date (Web): 02 Nov 2018 Downloaded from http://pubs.acs.org on November 5, 2018

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Environmental Science & Technology

1

Underappreciated and complex role of nitrous acid

2

in aromatic nitration under mild environmental

3

conditions: the case of activated methoxyphenols

4

Ana Kroflič,*,a Matej Huš,*,b,c Miha Grilc,c,d and Irena Grgića

5 6

a

7

Ljubljana, Slovenia

8

b

9

Gothenburg, Sweden

Department of Analytical Chemistry, National Institute of Chemistry, Hajdrihova 19, SI-1000

Department of Physics, Chalmers University of Technology, Fysikgränd 3, SE-412 96

10

c

11

Hajdrihova 19, SI-1000 Ljubljana, Slovenia

12

d

13

Germany

Department of Catalysis and Chemical Reaction Engineering, National Institute of Chemistry,

Institute of Chemical Technology, Leipzig University, Linnéstraße 3, DE-04103 Leipzig,

14

1 ACS Paragon Plus Environment


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ABSTRACT

16

Many ambiguities surround the possible mechanisms of colored and toxic nitrophenols formation

17

in natural systems. Nitration of a biologically and environmentally relevant aromatic compound,

18

guaiacol (2-methoxyphenol), under mild aqueous-phase conditions (ambient temperatures, pH 4.5)

19

was investigated by a temperature-dependent experimental modeling coupled to extensive ab initio

20

calculations to obtain the activation energies of the modeled reaction pathways. The importance of

21

dark non-radical reactions is emphasized, involving nitrous (HNO2) and peroxynitrous (HOONO)

22

acids. Oxidation by HOONO is shown to proceed via a non-radical pathway, possibly involving

23

the

24

MP2/6-31++g(d,p) level, NO2• is shown capable of abstracting a hydrogen atom from the phenolic

25

group on the aromatic ring. In a protic solvent, the corresponding aryl radical can combine with

26

HNO2 to yield OH• and, after a subsequent oxidation step, nitrated aromatic products. The

27

demonstrated chemistry is especially important for understanding the aging of nighttime

28

atmospheric deliquesced aerosol. The relevance should be further investigated in the atmospheric

29

gaseous phase. The results of this study have direct implications for accurate modeling of the

30

burden of toxic nitroaromatic pollutants, and the formation of atmospheric brown carbon and its

31

associated influence on Earth’s albedo and climate forcing.

nitronium

ion

(NO2+)

formation.

Using

quantum

chemical

calculations

at

the

32


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33

INTRODUCTION

34

There has been much controversy regarding nitration mechanisms of aromatic compounds,

35

especially in complex and diverse biological and environmental systems. Because of extensive

36

industrial applications, aromatic nitration by electrophilic agents such as the nitronium and

37

nitrosonium ions (NO2+ and NO+, respectively) has in general been recognized as the most

38

thoroughly studied reaction in organic chemistry. However, it usually requires extreme

39

conditions.1 Nevertheless, a mounting debate on the exact mechanism of electrophilic aromatic

40

substitution (SEAr) persists.2-6 Considering natural compartments with a plethora of nitrogen-

41

containing reactive species (NRS; e.g. NO2+, NO+, NOx (NO• and NO2•) and NO3• radicals,

42

nitrous and peroxynitrous acids (HNO2 and HOONO), N2O3, N2O4), nitration pathways of

43

aromatic compounds at mild conditions are mechanistically even less understood.7-12

44

Bedini et al.13 have recently employed density functional theory (DFT) at the B3LYP level for

45

studying light-induced nitration of phenol and 4-chlorophenol in environmental waters. Based

46

on the calculations performed in the gaseous phase without accounting for solvation effects, the

47

authors ruled out the OH•-Ar adduct formation before the addition of NO2• to the aromatic ring.

48

Instead, nitration by NO2• alone was proposed. A direct NO2• addition to the aromatic ring and

49

the formation of the nitration product through the H-atom abstraction in a redox reaction that

50

involves NO2• as an oxidant did not describe the experimental observations appropriately. The

51

formation of a phenoxy radical by the first NO2• molecule and a subsequent recombination with

52

the second NO2• molecule seemed most likely. Several other scientists have also proposed an

53

aromatic nitration through the formation of a phenoxy radical in the atmosphere and biological

54

systems rather than the OH•-Ar adduct formation in the first reaction step of aromatic nitration

55

(note: daytime OH• or nighttime NO3• was always required in the first step of the phenoxy

56

radical formation).14-18 In contrast, Zhang et al.19 suggest a water-assisted addition of NO2• to 3 ACS Paragon Plus Environment


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the OH•-Ar or NO3•-Ar adducts in the gas-phase formation of nitrated polycyclic aromatic

58

hydrocarbons. The reaction between the light-excited nitrophenols and NO2• in the presence of

59

oxygen has further been proposed for the formation of dinitrophenol in atmospheric waters.20

60

In phenol-containing HNO2 solutions, nitro- and nitrosophenols form in the dark even at

61

moderate pH, which is consistent with the formation of intermediates in a direct reaction

62

between phenol and HNO2.21 The same has been observed for catechol (CAT, 1,2-

63

dihydroxybenzene).22 Notwithstanding, we have recently ruled out a direct HNO2-driven

64

mechanism of guaiacol (GUA, 2-methoxyphenol) nitration under similar reaction conditions

65

and proposed that electrophilic nitration pathways prevailed in the dark.10 An analogous

66

mechanism has been suggested for the nitration of phenol by HNO2 in the presence of hydrogen

67

peroxide by Vione et al.23

68

Nitroaromatic compounds are well known for their environmental toxicity, carcinogenicity

69

and mutagenicity, and secondary production in the environment.24,25 It has been shown that

70

nitrophenols might be co-responsible for the decline of remote forests downwind from emission

71

sources.26,27 In addition, atmospheric nitration of aromatic pollutants influences the formation of

72

secondary organic aerosol (SOA), which is known to contribute substantially to the existing gap

73

between field measurements and atmospheric models.28 Being an important contributor to

74

atmospheric brown carbon, nitroaromatics alter the absorption properties of the troposphere and

75

thus affect Earth’s energy balance, and directly contribute to climate forcing.29 Therefore, the

76

formation mechanisms of nitroaromatic pollutants under environmentally-relevant conditions

77

are of the utmost interest.

78

For further mechanistic insight into the processes of interest, extensive quantum chemical

79

calculations were carried out in addition to long-term temperature dependent kinetic modeling.

80

Namely, the classical schemes put forward by kinetic studies mostly account for stable

81

quantifiable intermediates, thus inevitably lumping together several elementary reaction steps in 4 ACS Paragon Plus Environment

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an apparent one. In this work, quantum chemical calculations at the MP2/6-31++g(d,p) level

83

were performed to better understand the mechanisms of electrophilic and radical nitration and

84

nitrosation of aromatic compounds in an aqueous medium. The theoretically calculated

85

activation energies of the rate-determining steps (i.e. the reactions between NRS and aromatic

86

molecules) were used in the recently developed predictive model of GUA nitration in

87

atmospheric waters10 to account for the temperature variation of the experimental data. It is

88

shown that in doing so we describe the new experimental dataset very well, confirming and

89

upgrading the theoretically postulated reaction scheme. We not only expand the current

90

understanding of aqueous-phase aromatic nitration under mild environmental conditions but

91

also propose a new non-radical pathway of phenols nitration in the dark where HNO2 plays a

92

pivotal role.

93

METHODS

94

Computational details. Theoretical quantum chemical calculations were performed using

95

Gaussian 09 program suite30 at the MP2/6-31++g(d,p) level.31-35 Some provisional calculations

96

were also performed with B3LYP density functional theory to check whether our choice of the

97

computational method was warranted. With the B3LYP calculations, we were able to locate

98

most, but not all, of the minima with matching geometries and relative energies to those from

99

the MP2 approach. B3LYP is, however, known to miss some energy minima in organic

100

reactions as it underestimates dispersion interactions. Specifically for aromatic nitration, it has

101

been previously pointed out that B3LYP falls short of identifying all stationary points.3

102

Computationally expensive methods, such as single and double excitation coupled cluster

103

(CCSD), reveal all stationary points and arguably give better thermochemistry and geometries,

104

but are prohibitively time-consuming on larger systems with many stationary points. As a

105

compromise, MP2/6-31++g(d,p) was chosen in our case. A comparison of our results with other 5 ACS Paragon Plus Environment


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CCSD calculations on benzene nitration shows that we have located analogous stationary points

107

and recovered comparable energetics, proving that the choice of the method was reasonable.2

108

As shown by Jurečka et al.,36 the difference in energy between MP2 and CCSD(T) is less than 3

109

kJ mol–1, which we take as a 95% confidence interval in our predictive model for the values

110

obtained from the quantum calculations.

111

To account for the aqueous environment of the reactions under consideration, we used a

112

polarizable continuum model (PCM) with the effective dielectric constant 78.5 (the default

113

parameter for water), where solute cavities are embedded as a set of overlapping spheres.

114

Thermochemistry was calculated with zero-point energy taken into account. We report the

115

energetics and thermodynamic quantities relative to the infinitely separated reactants (GUA

116

derivatives and relevant ions or radicals).

117

The intermediates and transition states (TS) were fully optimized without constraints. TS were

118

obtained with the synchronous transit-guided quasi-Newton method (STQN). Vibrational

119

analysis was used to confirm that intermediates had only real frequencies and were thus located

120

in the minima of the potential energy surface (PES), while TS were saddle points and had

121

exactly one imaginary frequency corresponding to the desired reaction pathway. They were

122

confirmed by integrating the intrinsic reaction coordinate (IRC) in both directions from the TS,

123

ending up in products and reactants, respectively.

124

Recombination of radicals is a non-activated process without a saddle point on the PES. The

125

opposite holds true for fragmentation. However, an activation barrier can be found if one

126

considers that this is an example of a spin-forbidden reaction occurring on two potential energy

127

surfaces. The initial triplet state of two separated radicals “hops” into the singlet state at the

128

minimum energy crossing point (MECP), which is an adiabatic transition state. The reaction

129

barrier was defined as the energy at the MECP relative to the initial state (i.e. separated radicals

130

for recombination or stable molecule for fragmentation).37 6 ACS Paragon Plus Environment

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Laboratory experiments. The temperature dependence of GUA nitration in a moderately

132

acidic NaNO2/H2SO4 solution (pH 4.5) was investigated in the dark and under simulated

133

sunlight conditions. The experiments were performed at four different temperatures (283, 293,

134

298, and 303 K; the data at 298 K are taken from our previous work27) and the proposed

135

reaction model was fitted to the experimental data points with high precision (see also Kinetic

136

modeling section). For details see SI, page S1.

137

Kinetic modeling. The influence of temperature on the kinetics of nitration and nitrosation of

138

GUA and its primary reaction products (i.e. nitro and nitrosoguaiacols) was quantitatively

139

explored by the recently developed kinetic model for the reactions performed at 298 K.10 In

140

order to minimize the correlation between the activation energy and the pre-exponential factor

141

during the regression analysis, kinetic rate constants were determined according to a modified

142

Arrhenius equation:

143

∙ 𝑒𝑥𝑝 ― 𝑘𝑇𝑖 = 𝑘298K 𝑖

144

where k and Ea are the kinetic rate constant and activation energy, respectively, R is the gas

145

constant, and i and T denote the reaction number (see column i in Table 1) and the experimental

146

temperature, respectively. The rate constants for all reactions i at 298 K (𝑘298K ) were taken from 𝑖

147

our previous work and were not subjected to further regression analysis.10 The activation

148

energies accounting for the temperature dependence in the model were determined either by

149

regression analysis (mainly electrophilic nitrosation), by ab initio calculations (regiospecific

150

electrophilic and radical nitration and nitrosation of GUA and its primary reaction products) or

151

both (NO•, NO2•, NO+, and NO2+ formation and termination reactions). The set of differential

152

molar balances postulated according to the proposed reaction scheme was numerically solved in

153

Matlab 7.12.0 (MathWorks, Natick, MA, USA). The Levenberg–Marquardt and Jacobian

(

𝐸a𝑖 1 𝑅 𝑇

(

1

― 298K

))

(1)



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154

matrix computation methods were used for the regression analysis (parameters optimization)

155

and the subsequent determination of the 95% confidence intervals.

156

RESULTS

157

Experimental-modeling study.

158

The proposed macroscopic reaction scheme of GUA nitration in a moderately acidic NaNO2

159

solution (above the pKa of nitrous acid) is shown in Figure 1.10,27 So far, the model has been

160

verified with data measured at 298 K, whereas this study represents an extension to the

161

temperature dependence in the range from 283 to 303 K. The experimental data at 283, 293,

162

298, and 303 K together with the modeling results are gathered in Figure 2 (nighttime and

163

daylight conditions), showing a remarkably good agreement and offering convincing evidence

164

that the postulated mechanism and the derived activation barriers are sound. We shortly point

165

out a few observations that led us to extend the study to theoretical computations and

166

importantly contribute to the understanding of the nitration of phenolic compounds in natural

167

systems.

168 169

Figure 1. The proposed macroscopic reaction scheme of guaiacol (GUA) aging in a moderately

170

acidic NaNO2 solution. The reaction pathways according to the electrophilic and radical

171

reaction mechanisms are presented with dashed and solid arrows, respectively. The numbers 8 ACS Paragon Plus Environment

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172

correspond to the kinetic rate constants gathered in Table 1. The identified reaction products are

173

shown in black: 4-nitroguaiacol (4NG), 6-nitroguaiacol (6NG), and 4,6-dinitroguaiacol (DNG).

174

The nitrosoguaiacol (NOG) and nitronitrosoguaiacol (NONG) sideproducts according to the

175

model are colored grey. (Data used from Ref.27)

176

The activation energies, determining the temperature dependence of the kinetic rate constants

177

at 298 K, were first optimized by the regression analysis. We found that the system was

178

insensitive to the variation of Ea of the radical reactions (1–4 and 13 in Table 1) as long as these

179

activation energies were the same or very similar and the ratio between the respective kinetic

180

rate constants remained unchanged. The activation energy of the NO2• formation is the rate-

181

limiting step and determines the influence of temperature on the global nitration rates, whereas

182

the selectivity of the respective radical reactions is governed by the pre-exponential Arrhenius

183

factors, describing the probability of successful collisions. This is consistent with our past

184

observation that the ratio between the radical nitration rate constants is important, not the

185

absolute values.10 Therefore, the activation energies of the reactions between the aromatic

186

components and each reactive species considered in the model were ultimately determined by

187

quantum chemical calculations and used in the modeling. The activation energies obtained from

188

either the quantum chemical calculations and/or experimental modeling (the latter mainly for

189

lumped reactions) are gathered in Table 1 and match the experimental data very well (Figure 2).

190

In the absence of hydrogen peroxide and illumination, the activation energy of the NO2+

191

formation is the highest among all the considered reactive species (Ea22 = 34 kJ mol–1). This

192

means that the cumulative formation of the electrophilic nitronium ion in the dark is most

193

influenced by the reaction temperature, which results in a limited contribution of this reaction

194

pathway at 283 K. Moreover, a relatively large confidence interval is reported for the rate

195

constant of this lumped reaction (k22, Table S1), implying that the overall influence of the

196

electrophilic aromatic nitration on the measured concentration profiles is weak. An additional 9 ACS Paragon Plus Environment


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197

consideration from the quantum chemical calculations suggests that the present mechanistic

198

representation at the given experimental conditions is not necessarily exact; a novel mechanism

199

is proposed in the following sections.

200

The addition of H2O2 significantly increases the formation of NO2+ at higher temperatures, but

201

still has a negligible effect at 283 K, which is reflected in the high activation energy (Ea29 = 94

202

kJ mol–1) of the lumped reaction of the conversion of HNO2 and H2O2 into HOONO (and

203

presumably further to NO2+). All lumped reactions of the NRS formation/degradation

204

considered in the model are summarized in Scheme S1 and Table S1.

205

In contrast, the low activation energies for the formation of radicals in the dark (Ea20 = 26 kJ

206

mol–1) and under illumination (Ea32 = 22 kJ mol–1) imply that temperature has relatively little

207

effect on these lumped reactions. The modeled values are mostly consistent with our

208

calculations and the literature data for environmental systems.38 The addition of H2O2 also

209

shows an insignificant effect on the formation of radicals; k27 for the NO2• formation is

210

negligible,10 alongside the high energy barrier required for the formation of NO• (Ea28 = 140 kJ

211

mol–1). This opposes many interpretations of aromatic nitration induced by biologically

212

important HOONO,39 but is, however, consistent with a recent understanding, proposing the

213

non-radical nitration mechanism.12


Page 11 of 34


a)

b)

10 °C

0.08 0.04

0.04 0.00 0.08

20 °C

0.04 0.00 0.08

Conc. (mM)

Conc. (mM)

0.00 0.08

25 °C

0.00 0.08

0.04 0.00 0.08

25 °C

0.00 0.08

30 °C

30 °C

0.04

0.04

214

20 °C

0.04

0.04

0.00

GUA 4NG 6NG DNG

10 °C

0.08

0

10

20

30

40

0.00

0

10

20

30

40

Time (h)

Time (h)

215

Figure 2. Experimental data (symbols) of guaiacol (GUA) nitration in a slightly acidic H2SO4

216

solution (pH 4.5) upon the addition of 1 mM NaNO2 and H2O2 a) in the dark and b) under

217

simulated solar irradiation at 283, 293, 298, and 303 K, and the modeled curves (solid lines)

218

according to the proposed reaction scheme. The following main reaction products were

219

quantified: 4-nitroguaiacol (4NG), 6-nitroguaiacol (6NG), and 4,6-dinitroguaiacol (DNG).

220

(Data at 298 K used from Ref.27)



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221

Table 1: The best-fit kinetic rate constants (k, ' denotes the electrophilic reaction mechanism) and

222

activation energies (Ea) reported with a 95% confidence interval valid at the experimental conditions at

223

pH 4.5. A method of obtaining Ea is also reported: calculations at the MP2/6-31++g(d,p) level (ab

224

initio) or regression analysis (RA). The rate constants of the corresponding lumped reactions are shown

225

in Table S1. i

NRS

product

ri

kia

Eai (kJ mol–1)b

method

Basic conditions

226 227 228 229 230

1

NO2•

4NG

k1∙[GUA]∙[NO2•]

(4.01 ± 0.04) × 109 L mol–1 s–1

21 ± 3

ab initio

1'

NO2+

4NG

k 1'∙[GUA]∙[NO2+]

(2.52 ± 0.01) × 105 L mol–1 s–1

15 ± 3

ab initio

2

NO2•

6NG

k 2∙[GUA]∙[NO2•]

(5.74 ± 0.04) × 109 L mol–1 s–1

21 ± 3

ab initio

2'

NO2+

6NG

k 2'∙[GUA]∙[NO2+]

(4.07 ± 0.01) × 105 L mol–1 s–1

48 ± 3

ab initio

3

NO2•

DNG

k 3∙[4NG]∙[NO2•]

(7.04 ± 0.08) × 108 L mol–1 s–1

21 ± 3

ab initio

3'

NO2+

DNG

k 3'∙[4NG]∙[NO2+]

(1.42 ± 0.01) × 101 L mol–1 s–1

63 ± 3

ab initio

4

NO2•

DNG

k 4∙[6NG]∙[NO2•]

(1.190 ± 0.009) × 108 L mol–1 s–1

21 ± 3

ab initio

4'

NO2+

DNG

k 4'∙[6NG]∙[NO2+]

(7.01 ± 0.04) × 102 L mol–1 s–1

39 ± 3

ab initio

5

NO2+, NO2−

DNG

k 5∙[GUA]∙[NO2+]∙[NO2−]

(3.03 ± 0.03) × 103 L2 mol–2 s–1

28 ± 8

RA

6

n.a.

unknown

k 6∙[DNG]

(7 ± 1) × 10–6 s–1

21 ± 5

RA

10

NO•

NOG

k 10∙[GUA]∙[NO•]

(6.65 ± 0.05) × 109 L mol–1 s–1

139 ± 3

ab initio

10'

NO+

NOG

k 10'∙[GUA]∙[NO+]

(5.46 ± 0.04) × 102 L mol–1 s–1

57 ± 4

RA

11

NO•

NO4NG

k 11∙[4NG]∙[NO•]

(9.18 ± 0.08) × 108 L mol–1 s–1

139 ± 3

ab initio

12

NO•

NO6NG

k 12∙[6NG]∙[NO•]

(3.86 ± 0.03) × 109 L mol–1 s–1

139 ± 3

ab initio

13

NO2•

NONG

k 13∙[NOG]∙[NO2•]c

(1.095 ± 0.007) × 1010 L mol–1 s–1

21 ± 3

ab initio

13'

NO2+

NONG

k 13'∙[NOG]∙[NO2+]c

(4.09 ± 0.05) × 104 L mol–1 s–1

33–55d

ab initio

a

Data taken from Refs. 10,27

b

The confidence interval for ab initio values is estimated to be 3 kJ mol–1 based on benchmarking MP2 against CCSD(T)

(see Computational details section).36 c

The model does not distinguish between 4- and 6-nitrosoguaiacol. The apparent kinetic rate constant for nitration of both

NOG isomers is reported.


Page 13 of 34

231 232 233

d


Two distinct activation energies were computationally determined for 4NOG and 6NOG nitration, and Ea corresponding to

the apparent kinetic rate constant of their nitration is dependent on the ratio between both isomers; namely, it falls within the reported interval.



Page 14 of 34

234

Quantum chemical calculations.

235

Electrophilic aromatic substitution: reaction mechanism. In the absence of UV light or other

236

sources of radical species, nitration of aromatic compounds proceeds primarily as an

237

electrophilic substitution reaction and, as a rule, requires a strongly acidic medium.1

238

Nevertheless, an electrophilic mechanism of aromatic nitration has also been suggested at

239

milder conditions.10,23 Although SEAr is one of the most well-known and researched reactions in

240

organic chemistry, the mechanistic subtleties are still being debated. Wheland40 proposed the

241

existence of a protonated benzene derivate (σ-complex), which is the key intermediate in most

242

proposed mechanisms.41-46 How it forms, however, differs markedly among the mechanisms.

243

Some propose the formation of different weakly bound intermediates before the formation of

244

the Wheland intermediate, while others favor a single-electron-transfer pathway. Experimental

245

data are inconclusive but theoretical studies seem to favor the latter option.47,48 Although NO2+

246

and NO+ possess similar geometry, electrochemistry, and activity, they are vastly different in

247

their reactivity towards aromatic compounds.2,49 This is a consequence of different reaction

248

pathways, whereas electrophilic aromatic nitrosation displays fewer intermediates and higher

249

saddle-point energies than nitration, which is described in the following sections.50

250

Electrophilic nitration of GUA was first examined. The nitronium ion can approach GUA

251

perpendicularly, forming a weakly bound π-complex 1 (Figure S1). In this structure, common to

252

all nitration pathways for different aromatic sites, the interaction between the delocalized

253

electron system and nitronium ion is weak and the reactants geometries remain unperturbed.

254

This complex is readily formed in a non-activated step, as it is also the case in electrophilic

255

nitration of benzene.51 It quickly converts through transition states 2* and 3* to two different -

256

reactant complexes 4 and 5, respectively, in a non-rate limiting step. In these structures, the

257

nitronium group assumes a bent structure above the ring, halfway between the C1-C2 or C4-C5

258

atoms, respectively. The following step was found to be rate-limiting.52 Activation energies for 14 ACS Paragon Plus Environment

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the conversion of 4 and 5 through 6* and 7* to 8 and 9 were calculated to be +15 and +48 kJ

260

mol−1, respectively, as shown in Figure 3a. The proton abstraction from these Wheland

261

intermediates to yield the end-products, 4NG and 6NG, is known to be a fast, non-rate limiting

262

step and is mediated by the solvent.3 As mentioned before, we deemed these values to be

263

insensitive to temperature in the investigated regime and used them as the activation energies

264

for the reaction rate constants k1’ and k2’, respectively.

265

It should be noted that the formation of 4NG has a much lower energy barrier than 6NG

266

(Figure 3), from which it follows intuitively that 4NG is kinetically favored over 6NG. In fact,

267

this is not consistent with our experimental results (Figure 2a), which agree with the positional

268

selectivity of diffusion-controlled SEAr reactions (o > p >> m in respect to the most activating

269

hydroxyl group on the aromatic ring).53 Nevertheless, the experimental data can be reconciled

270

with the theoretical calculations if the stability of both intermediates is taken into account.

271

Namely, the precursor -complex of 6NG (5) is thermodynamically much more stable than that

272

of 4NG (4). As provisionally shown in Figure 3a, 4 can and does quickly convert into 5 with

273

virtually no activation barrier. This means that although having to traverse a higher saddle point

274

7*, 9 is preferably formed as its precursor 5 exists in larger amounts than 4. Still, at higher

275

temperatures, the preferential formation of the thermodynamically more stable product (4NG) is

276

expected.

277

Electrophilic nitration of the nitrated GUA derivatives also proceeds at the given reaction

278

conditions; both 4NG and 6NG are readily nitrated into DNG (reactions k3’ and k4’). The

279

mechanism includes analogous intermediates and transition states as in the nitration of GUA

280

(for details and structures 10–29 see Figures S2–S3). Activation energies of +63 and

281

+39 kJ mol−1 were calculated for the nitration of 4NG and 6NG, respectively, as shown in

282

Figure 3c. Nitration of 6NG is predicted to be faster than that of 4NG, which is consistent with



Page 16 of 34

283

our experimental results (see Figure 2b and compare the decays of both products after GUA has

284

been completely consumed).

285 286

Figure 3. Graphical representation of the potential energy surface for the electrophilic nitration

287

of

288

(c) 4-nitrosoguaiacol (4NOG) and 6-nitrosoguaiacol (6NOG), and for the (d) electrophilic

289

nitrosation of guaiacol (GUA). Only nitration/nitrosation on ortho (red solid line) and para

290

(blue dashed line) positions are considered. The compounds labeled as in Figures S1–4.

(a) guaiacol

(GUA),

(b) 4-nitroguaiacol

(4NG)

and

6-nitroguaiacol

(6NG)

291

Electrophilic nitration of the nitroso-substituted GUA was investigated in the same manner

292

(for details see SI, pages S5–S6). The formation of 4-nitro-6-nitrosoguaiacol (Ea = +33 kJ

293

mol−1) is again predicted to occur faster than that of 6-nitro-4-nitrosoguaiacol (Ea = +55 kJ

294

mol−1), which is presented in Figure 3b. Since our experimental apparatus was not able to

295

distinguish between the two products, their kinetics was lumped in one apparent reaction k13’.


Page 17 of 34


296

These calculated activation energies were used in our kinetic model, while the activation

297

energy of the lumped reactions involved in NO2+ formation from HNO2 was determined by the

298

regression analysis.

299

Similarly to what has been described for nitration, electrophilic aromatic nitrosation begins

300

with a weakly bound π-complex between GUA and NO+ (30, Figure S4); the nitrosonium ion is

301

positioned above the ring and its nitrogen atom is interacting with the π-electrons. This adduct

302

then transforms into protonated nitrosoguaiacols (33 and 34) in a single elementary rate-

303

determining step (see Figure 3d for the PES). As already pointed out by Skokov and Wheeler,50

304

the transient Wheland structure in the reaction of nitrosation is not a true intermediate but

305

merely a transition state (31* and 32*). The activation energies in this mechanism are

306

+263 kJ mol−1 and +309 kJ mol−1 for the formation of 4NOG and 6NOG, respectively,

307

corresponding to the lumped k10’ in our model. This is consistent with known facts and our

308

experimental findings that electrophilic nitrosation proceeds several orders of magnitudes

309

slower than nitration, and in line with the theoretical results from Gwaltney et al.2 The final

310

abstraction of proton is again a fast reaction.

311

In our model, however, the activation energy of this reaction was determined by regression

312

analysis to fit the experimental results better. Note that the authors had avoided the introduction

313

of OH• in the predictive model on purpose, i.e. to reduce the degrees of freedom and improve

314

the predictive power of the model with regard to aromatic nitration.10 This compensates for the

315

high activation energies of electrophilic nitrosation with the Ea of hydroxylation (21 kJ mol−1)

316

and results in the experimentally determined Ea10’ of 57 kJ mol−1.

317

Homolytic aromatic substitution: the reaction mechanism. Homolytic aromatic substitution

318

reactions prevail under daytime conditions because radical species mainly form photolytically;

319

including OH• as the most important radical in the environment. This chemistry is, however,

320

always accompanied by electrophilic and other non-radical reactions (e.g. oxidation-reduction 17 ACS Paragon Plus Environment


Page 18 of 34

321

reactions) that are insensitive to light. There are several possible pathways for the formation and

322

interconversion of radicals. However, radical reactions are generally fast enough for their

323

observed rate to be determined by transport phenomena (see for instance the calculated barriers

324

for the recombination reactions below). With this in mind, an approximate uniform value of 21

325

kJ mol–1 was chosen as the activation energy of radical reactions in the predictive model (Table

326

1), which is consistent with the quantum chemistry calculations (vide infra the reaction of GUA

327

with NO2•). For clarity, only the reactions pertaining to the para site are elaborated henceforth.

328

The ortho site is reactive in a similar fashion.

329

Initiation. In the environment, GUA can react with various radical species, including OH•,

330

NO3• and, theoretically, NO• and NO2•. When OH• is present in large quantities, it readily and

331

barrierlessly attaches to aromatic carbon atoms due to high stabilization energy. The results of

332

ab initio calculations presented in the SI show that there is little preference as to where OH•

333

binds (structures 35–40 in Figure S5). It is slightly more favorable, however, for OH• to bind to

334

the hydroxyl-bearing carbon atom (C1), yielding 35. This agrees with the subsequent findings

335

that radical reactions begin with H• being cleaved off the OH group (vide infra). The

336

stabilization energies of these isomers with respect to the isolated reactants range from −65 to

337

−86 kJ mol−1.

338

In contrast to the general perception that NO2• is too weak to react with aromatic compounds,

339

our calculations support the work of Bedini et al.13 and demonstrate that NO2• is not only

340

capable of abstracting hydrogen atoms from GUA while turning itself into HNO2, but also that

341

this is the prevailing mechanism of the GUA-derived radicals formation in the dark. NO2• most

342

likely abstracts the hydrogen atom from the GUA hydroxyl group. It first forms a weakly bound

343

(3 kJ mol–1) planar adduct (41), which has the activation barrier of 21 kJ mol–1 (42*) for

344

hydrogen abstraction, yielding a phenoxy radical (43, Figures S8–S9) and HNO2. As this

345

reaction has the lowest barrier among all involving radicals and GUA, we believe this is the 18 ACS Paragon Plus Environment

Page 19 of 34


346

main pathway in the radical nitration mechanism initiated by NO2•. Thus, this activation barrier

347

was used in our mechanistic model to describe the radical reactions. Interestingly, despite OH•

348

being much more reactive than NO2•, the activation barrier for the phenoxy radical formation

349

following the attack of OH• is much higher (69 kJ mol–1; see SI, Figures S6 and S8, and page S8

350

for details); this can be explained by the high stabilization energy of the GUA-OH• adducts (35–

351

40).

352

Alternatively, NO2• might abstract the aromatic hydrogen atom. The adduct of NO2• at the

353

para position of GUA (44) does not exhibit any stabilization (less than 1 kJ mol–1) and has a

354

prohibitively high activation energy of 150 kJ mol–1 (45*), which yields non-negligible amounts

355

of aryl species via direct hydrogen abstraction (46, Figures S8–S9). A solvent-mediated

356

isomerization from the phenoxy radical is thus a more likely way of the aryl radical formation.

357

It is even less likely for NO2• to substitute the hydroxyl group. A weakly bound π complex

358

(47) with negligible stabilization energy would have to overcome the barrier (48*) of 169 kJ

359

mol–1 for NO2• to displace the hydroxyl group which would migrate to the adjacent carbon atom

360

(49). The ensuing 2-nitroanisol (50) and OH• radical are by 165 kJ mol–1 less stable than GUA

361

and NO2• when completely separated; this is expected as NO2• is a better leaving group than

362

OH•. It is also not possible for NO2• to insert directly to the para position via transition state 51*

363

and yield a hydrogenated 4NG•H (52) as the required activation energy exceeds 220 kJ mol–1

364

(Figure S10).

365

NO3•-driven nitration is one of the generally accepted pathways for the formation of

366

nitroaromatic compounds in the environment. The NO3• radical is much more reactive than

367

NO2•; it is predominantly a nighttime oxidant (it rapidly photolyses during the day) but was not

368

present in our experimental system. For the sake of completeness, we studied its reactions as

369

well (Figures S11–S12). To sum up the results of the quantum chemical calculations presented

370

in the SI (page S12): if NO3• were present in the reaction mixture, it would considerably speed 19 ACS Paragon Plus Environment


Page 20 of 34

371

up the reaction, generating 43 and 46 (and the corresponding isomers) orders of magnitudes

372

faster.

373

NO• behaves in a similar fashion as NO2•; however, due to its lower reactivity, the reactions

374

are much slower. For instance, upon weakly interacting with the hydroxyl hydrogen (53), the

375

activation barrier for the abstraction (54*) of this hydrogen is 139 kJ mol–1. Moreover, the

376

ensuing HNO and phenoxy radical (43) are by 126 kJ mol–1 less stable than the reactants. Also,

377

the substitution of the hydroxyl group by NO• (55*) would require surmounting the activation

378

energy of 214 kJ mol–1 to displace the OH group to the adjacent carbon atom (56) and

379

ultimately yield 2-nitrosoanisol (57). Similarly, a direct insertion of NO• in para position (58*)

380

to yield a hydrogenated 4NOG•H (59) is inaccessible with a barrier of 213 kJ mol–1 (Figure

381

S13).

382

Propagation. Once the aryl radical of GUA (such as 46) is formed through the solvent-

383

mediated isomerization of the phenoxy radical (possibly via a carbocation radical intermediate;

384

see Figure S14 and Hemberger et al.54) or by the OH• attack on the unsubstituted carbon atoms

385

(cf. Figures S6–S7), it can react with HNO2 or, less readily, HNO3 (for reactions with radical

386

species vide infra) and form nitroso and nitro products. With HNO2, the hydrogenated 4NG•H

387

(52) is formed extremely fast as the activation barrier (60*) is only 9 kJ mol–1. HNO3, however,

388

has to overcome a barrier of 73 kJ mol−1 (61*) to form the 4NG•OH adduct with the hydroxyl

389

group attached to the adjacent (in position meta) carbon atom (62). For structures, see Figure

390

S15.

391

Lastly, the hydrogenated 4NG•H (52) converts into either 4NG or 4NOG. To form 4NG, the

392

hydrogen atom from the nitro group must first migrate (63*) to the adjacent carbon atom (64) or

393

be cleaved off by another radical. The activation energy for its migration is high (162 kJ mol–1)

394

and it is thus more likely that the hydrogen is cleaved off by NO• (65*) or NO2• (66*) with the

395

activation barriers of 44 and 39 kJ mol−1, respectively. Alternatively, the N-O bond in the 20 ACS Paragon Plus Environment

Page 21 of 34


396

protonated nitro group can also break, resulting in the migration of the OH moiety (67*) to the

397

adjacent carbon atom (68), which ultimately yields 4NOG. Such rearrangement has a lower

398

activation barrier (126 kJ mol–1) and helps explain why nitroso products are formed despite the

399

NO• radical being much less reactive than NO2•. Similarly as 4NG•H, the hydrogenated

400

4NOG•H (59) can lose its hydrogen atom through the attack of NO• (69*) or NO2• (70*) with the

401

activation barriers of 89 and 58 kJ mol−1. See Figure S16 for structures. The formed

402

nitrosoaromates are readily oxidized to their respective nitro analogoues.55 This has been

403

recently considered as one of the competitive mechanisms in the CAT nitration under similar

404

experimental conditions.22

405

Termination. Ultimately, radical reactions come to a halt when two radicals recombine.

406

Activation barriers, defined as the energy of the MECP (Figure S17) for the association of aryl

407

radical (46) and the nitrogen-containing radicals (i.e. NO2• and NO•), are gathered in the SI

408

(page S16), together with the corresponding transition states presented in Figure S18. However,

409

the termination reactions (recombination) are so fast that they are essentially transport-limited

410

and the barriers given in the SI are not rate-determining for our model. As expected for radical

411

reactions, the termination steps occur when the concentration of the radicals increases relative to

412

the concentration of the reactants, which typically happens in the latter stages of the reaction.

413

DISCUSSION

414

Pathways of aromatic nitration. NO2• is shown capable of reacting with activated phenol,

415

which has not been generally accepted yet. Still, daytime OH• and nighttime NO3• are much

416

stronger oxidants. NO• is not reactive enough on its own: however, it is important in the

417

subsequent reaction steps. For a complete scheme of the studied radical reactions, refer to

418

Figure 4.



Page 22 of 34

419

To summarize the most important conclusions regarding the studied nitration, the relevance of

420

which for atmospheric nighttime chemistry should be considered in the future; if NO3• were

421

present in the solution, it would be the main source of the GUA-derived radicals in the dark. In

422

its absence, NO2• solely is responsible for producing reactive aryl radicals and does not directly

423

substitute the groups on the aromatic ring. NO2• rather reacts with GUA and forms the

424

corresponding phenoxy radical (GUA-O•), which further isomerizes to its aryl analogue

425

(GUA•-OH) in a solvent-mediated step. It can also recombine with other radical species in

426

solution. Nevertheless, the coupled oxidation-reduction reaction involving HNO2 substantially

427

increases the importance of the nighttime nitration of activated phenols by NO2• in low

428

concentration. GUA•-OH can combine with HNO2 to form 4- and 6-nitrosoguaiacols (NOG),

429

which are relatively easily oxidized to the respective nitroderivatives (4NG and 6NG; e.g. with

430

HNO2 or NO2•, concomitantly forming NO•, which is not strong enough to further react with

431

present aromatics). See Scheme 1 for the set of relevant reactions.


Page 23 of 34


432 433

Figure 4. A complete reaction scheme of the studied radical reactions involving GUA and NRS.

434

For clarity, only the attack on para site and formation of mono-substituted products is

435

considered. The colored values in italics (green for accessible, red for inaccessible) show the

436

activation energies of the steps in kJ mol−1, as obtained from our ab initio calculations.

437

Thermolysis of HNO2 and the consumption of the unstable by-product HNO are also shown.

438

In the presence of H2O2, however, it has recently been shown feasible that an electrophilic

439

nitrogen, presumably NO2+, forms under mild atmospheric conditions. Even upon the in-situ

440

formation of H2O2 from oxygen in a redox system of (hydro)quinones, such as CAT.10 We

441

generally confirm the electrophilic mechanism of GUA nitration in the presence of H2O2.

442

Notwithstanding, as only traces of CAT impurity were present in the GUA solution, the dark

443

reaction performed in the absence of oxygen and H2O2 suggests rather the existence of an 23 ACS Paragon Plus Environment


Page 24 of 34

444

equilibrium which opposes the GUA nitration if the solution is not aerated. The corresponding

445

experiment performed under N2 atmosphere (O2 was completely expelled from the reaction

446

medium) is shown in Figure S19 and the mismatch between the experimental data and the

447

predictive model at longer reaction times can be nicely explained by the reactions summarized

448

in Scheme 1.

449

2 HNO2 ↔ NO• + NO2• + H2O

450

GUA + NO2• ↔ GUA-O• + HNO2

451

GUA-O• ↔ GUA•-OH

452

GUA•-OH + HNO2 → NOG + OH•

453

NOG + HNO2 → NG + NO• + H+

454

NO•(aq) + [O] ↔ HNO2

455

Scheme 1. Complex role of HNO2 in guaiacol nitration.

456

It is well known that HNO2 reversibly thermolyses to NO• and NO2• in aqueous solutions,56

457

which we also confirmed computationally (see the SI, page S18). The values agree very well

458

with Ea of the lumped reaction k20 for the formation of NO• and NO2• from HNO2 in the

459

equilibrium with NO2− (Table S1). In aerated aqueous solutions, HNO2 can regenerate from

460

NO• in the reaction with O2, whereas in the absence of oxygen NO• accumulates and stops the

461

production of NO2• by shifting the equilibrium towards HNO2. This agrees with our

462

observations, where in the absence of oxygen, GUA nitration initially proceeds, and stops after

463

some time.

464

A one-step oxidation of GUA by HNO2 (resulting in 43 or 46), however, was neither observed

465

experimentally nor could any suitable transition state be located computationally. The excess

466

concentration of HNO2 applied in this work would not allow such experimental system to 24 ACS Paragon Plus Environment

Page 25 of 34


467

respond in a switch-like manner (see Figure 2b), even though GUA is presumably more easily

468

oxidized than its nitrated analogues, which contain electron withdrawing substituents. Instead of

469

the delayed formation of DNG, its exponential production from the beginning of the experiment

470

would be expected, which could slightly accelerate after GUA would have been completely

471

consumed.

472

Environmental relevance. An approach coupling extensive experimental data collection, a

473

powerful experimental-modeling investigation and a comprehensive battery of quantum

474

chemical calculations on the mechanism of electrophilic and radical aromatic reactions

475

involving diverse NRS was employed to provide new insights into the nitration of activated

476

aromatic compounds under environmentally and biologically relevant conditions. The

477

represented results strongly support the current state of understanding that a HOONO induced

478

oxidation proceeds via the non-radical mechanism. Furthermore, a special role of HNO2 in the

479

dark formation of phenoxy radicals (through NO2• formation) and their further transformation

480

into nitrophenols, yielding also OH• (by reaction with HNO2 itself), is emphasized. In short,

481

after the phenoxy radicals are formed by trace NO2•, they isomerize to the aryl radicals that can

482

react with HNO2 to the immediate precursors of nitroso- and nitrophenols. The intermediate

483

nitrosophenols are ultimately oxidized to their corresponding nitrated products (again possibly

484

with HNO2), which are potentially toxic for living organisms and, if present in the atmosphere,

485

absorb solar and terrestrial irradiation. The overall influence of temperature on aromatic

486

nitration is small as the activation energies of the respective reactions are low to moderate.

487

Although the presented chemistry is especially important at low pH (e.g. in deliquesced

488

atmospheric aerosols, pH-dependent data not shown), it is demonstrated to be relevant also at

489

milder conditions, above the pKa of HNO2, which has not been generally recognized yet. The

490

authors want to underline the possible importance of the demonstrated HONO-mediated

491

chemistry also in the atmospheric gaseous phase, which brings novel aspects about the role of 25 ACS Paragon Plus Environment


Page 26 of 34

492

this emerging atmospheric pollutant. These findings, if included into atmospheric models,

493

would improve the description of the likely underestimated dark formation of nitrophenols in

494

the atmospheric models.

495 496

ASSOCIATED CONTENT

497

Supporting Information

498

The Supporting Information is available free of charge on the ACS Publications website at DOI:

499

Materials and methods; set of lumped reactions; structures of intermediates and transition

500

states; mechanisms of electrophilic nitration for 4NOG, 6NOG, 4NG and 6NG;

501

mechanisms of radical reactions involving OH•, NO2• and NO3•; activation energy

502

determination for radical reactions; coordinates of the located stationary points; phenoxy

503

radical isomerization, experiment in the absence of oxygen.

504

AUTHOR INFORMATION

505

Corresponding Authors

506

*E-mails: [email protected] and [email protected].

507

Notes

508

The authors declare no competing financial interest.

509

ACKNOWLEDGMENTS

510

The authors acknowledge the financial support from the Slovenian Research Agency (research core

511

funding Nos. P1-0034 and P2-0152). M.H. also wishes to thank the Knut and Alice Wallenberg

512

Foundation (Project 2015.0057) for funding and Matthias Vandichel for fruitful discussions regarding

513

the chemistry of radicals. 26 ACS Paragon Plus Environment

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514

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